The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration–approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006–April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.
Hyperinsulinism, the most common cause of persistent hypoglycemia in neonates, may result from underlying genetic causes1,2 or occur in infants who are small for gestational age, born to mothers with diabetes mellitus, or exposed to perinatal stressors.3 Severe hypoglycemia caused by hyperinsulinism can lead to brain injury and permanent cognitive disability.4,5 Hyperinsulinemic hypoglycemia (HH) is diagnosed by persistent hypoglycemia requiring a high glucose infusion rate (GIR) and inappropriately elevated insulin levels during hypoglycemia.6–9
Diazoxide is the first-line and only US Food and Drug Administration–approved, pharmacologic treatment of refractory hyperinsulinism. Diazoxide targets pancreatic β cells, binding to the sulfonylurea receptor-1 subunit of the KATP channel and inhibiting insulin release.6 Side effects of diazoxide include fluid retention (treated with chlorothiazide), hypertrichosis, neutropenia, thrombocytopenia, and pulmonary hypertension.10,11 To date, no clear association between diazoxide therapy and necrotizing enterocolitis (NEC) is known.7,10,11
Methods
Following institutional review board approval (IRB# 2018P001604), patients treated with diazoxide between April 2006 and April 2018 in our NICU were retrospectively identified in institutional pharmacy databases. The diagnosis of HH was made on the basis of blood glucose persistently <50 mg/dL, inappropriately detectable insulin level in the setting of hypoglycemia,7,8 and GIR >8 mg/kg per minute to maintain normoglycemia.8 The diagnosis of NEC was made per Vermont Oxford Network criteria12 with at least one clinical sign (bilious aspirate or emesis, abdominal distension, or occult or gross blood in the stool) and one abdominal radiograph (AXR) sign (pneumatosis, portal venous gas, or pneumoperitoneum).
Important clinical features that may contribute to the development of NEC13 were compared between patient cohorts who received diazoxide and did or did not develop NEC. Comparisons were made by Fisher’s exact test and Mann-Whitney U test without correction for multiple comparisons.
Results
Twenty-four infants were treated with diazoxide for HH in our NICU during the 12-year study period. The 5 infants who developed NEC were of younger gestational age (36.6 weeks versus 37.1 weeks, P = .03). Consistent with younger gestational age, infants who developed NEC had lower birth weight (2080 g versus 2930 g, P = .04), increased antenatal steroid exposure (40% versus 0%, P = .04), and less frequently received formula (60% versus 100%, P = .04). However, these differences did not remain after restriction of the analyses to infants older than 34 weeks (22 infants). There was no statistical difference between groups for other risk factors associated with NEC13 or etiology of HH (Table 1). In the following series, the cases of 5 infants exposed to diazoxide who developed NEC are reviewed. Additional case details are included in Table 2.
Case 1
A male infant born at 36 4/7 weeks’ gestation via cesarean for nonreassuring fetal heart tracing (NRFHT) developed hypoglycemia on day of life (DOL) one with serum glucose <45 mg/dL. He required a maximum GIR of 18.8 mg/kg per minute. On DOL2, insulin was 8.9 μIU/mL with serum glucose of 20 mg/dL. Diazoxide was started on DOL9. Full enteral feedings were reached on DOL15. On DOL19, he was diagnosed with NEC on the basis of abdominal distension, bilious aspirates, agitation, and portal venous gas and pneumatosis on AXR (Fig 1). Diazoxide was discontinued, and he was made nil per os (NPO) with bowel decompression and treatment with ampicillin, gentamicin, and clindamycin for 10 days. The infant recovered without surgery, and feedings were resumed on DOL30.
Case 2
A female infant born at 27 6/7 weeks’ gestation via emergent cesarean due to severe preeclampsia and NRFHT developed serum glucose <30 mg/dL on DOL1. She required a maximum GIR of 10.4 mg/kg per minute. During an episode of hypoglycemia to 33 mg/dL on DOL14, insulin was 4.1 μIU/mL, after which diazoxide and chlorothiazide were started. There was concern for NEC on DOL20, after she developed abdominal distension, bilious aspirates, and mucousy stools. AXR revealed distended bowel loops without pneumatosis. Diazoxide was discontinued. She improved after treatment with oxacillin, gentamicin, and clindamycin and bowel rest for 7 days. Enteral feedings were reintroduced on DOL27. Diazoxide was restarted on DOL35 for recurrent hypoglycemia. The infant did well until DOL45, when she developed recurrent NEC and rapidly decompensated. AXR revealed pneumatosis and portal venous gas (Fig 2). The infant developed hypoxemia and profound bradycardia, requiring resuscitation, including chest compressions and epinephrine. Emergent exploratory laparotomy revealed diffuse pneumatosis and small bowel perforation, which was resected. The bowel was placed in a silo for decompression. A subsequent arterial blood gas revealed profound metabolic acidosis with pH <6.7 and lactic acid of 20 mmol/L. Ten hours later, the infant again became bradycardic and developed asystole without response to cardiopulmonary resuscitation, epinephrine, and volume expansion. Resuscitation was discontinued and the infant died on DOL45.
Case 3
A female infant born at 36 5/7 weeks' gestation via emergent cesarean for NRFHT was admitted to the NICU for hypoglycemia, with lowest glucose level on DOL1 of 6 mg/dL. An insulin level during an episode of hypoglycemia to 25 mg/dL on DOL4 was 3.0 μIU/mL. The infant required a maximum GIR of 11.3 mg/kg per minute in addition to enteral feedings. Diazoxide and chlorothiazide were started on DOL6. She developed NEC on DOL8 with emesis, abdominal distension, tenderness, lethargy, tachycardia, hyponatremia, thrombocytopenia, and pneumatosis (Fig 3). Diazoxide and chlorothiazide were discontinued. She was made NPO and received ampicillin, gentamicin, and clindamycin for 7 days. After recovering from NEC, blood glucose stabilized on enteral feedings. However, during a safety fast on DOL27 before discharge, blood glucose fell below the safety threshold of 70 mg/dL.14 Diazoxide was restarted and continued after discharge until 7.5 months of age.
Case 4
A male infant born at 37 0/7 weeks' gestation via spontaneous vaginal delivery developed persistent serum glucose <50 mg/dL on DOL3, requiring a maximum GIR of 8.6 mg/kg per minute in addition to enteral feedings. An insulin level during an episode of hypoglycemia to 49 mg/dL on DOL4 was 1.4 μIU/mL. On DOL10, diazoxide and chlorothiazide were started. On DOL17, he developed skin discoloration, irritability, abdominal distension, hyponatremia, lactic acidosis, and anemia. AXR (Fig 4) and abdominal ultrasound revealed pneumatosis. He was made NPO, diazoxide was discontinued, and ampicillin, gentamicin, cefepime, and clindamycin were started. On DOL19, he developed abdominal distension and tenderness consistent with peritonitis, and antibiotics were changed to meropenem and vancomycin. An exploratory laparotomy revealed a small area of dusky bowel without necrosis; no resection was performed. The infant was found to have Escherichia coli bacteremia and Enterococcus bacteriuria. He received 14 days of antibiotics and bowel rest, after which feedings were resumed and blood glucoses stabilized without diazoxide.
Case 5
A male infant born at 28 0/7 weeks' gestation via cesarean for NRFHT and preeclampsia was found to have hypoglycemia with serum glucose <30 mg/dL starting on DOL1. He required a maximum GIR of 9.8 mg/kg per minute in addition to enteral feedings. An insulin level was 4.9 μIU/mL during an episode of hypoglycemia to 36 mg/dL on DOL36. He was started on diazoxide and chlorothiazide on DOL40. On DOL47, he developed abdominal distension, bloody stools, hyponatremia, and hypokalemia. AXR revealed abnormal bowel gas pattern with thickened bowel loops and pneumatosis in the transverse and descending colon (Fig 5). The infant was made NPO, diazoxide was discontinued, and he was treated with ampicillin, gentamicin, and clindamycin for 8 days. He was later found to be positive for norovirus via stool antigen testing and positive for an Enterococcus urinary tract infection. Ampicillin was given for a total of 10 days. Blood glucoses ultimately stabilized without diazoxide.
Discussion
Prompt treatment of HH is imperative to avoid poor neurodevelopmental outcomes,4,5 and diazoxide is the first-line and only pharmacologic therapy approved by the US Food and Drug Administration for HH.2 In this retrospective case series, we report 5 cases of NEC out of 24 neonates (20%) who received diazoxide; all cases were found in infants ≤37 weeks (Table 2). In our unit between 2009 and 2018, NEC was diagnosed in 1% of all inborn infants and 6% of all inborn very low birth weight infants, as recorded in the Vermont Oxford Network database.15
Authors of a recent retrospective study found 10 cases of NEC in 1066 NICU patients (0.9%) treated with diazoxide.11 However, neither the number of cases of NEC in patients with persistent hypoglycemia not treated with diazoxide nor their baseline incidence of NEC was reported. Furthermore, this retrospective cohort included cases without persistent hyperinsulinism. In two recent single-center studies of patients with HH, NEC was reported in 1 patient out of 295 (0.3%)1 and in 1 out of 194 patients (0.5%).10 Both studies included patients beyond the neonatal period. Recently, a case of NEC was described in a 35 3/7-week preterm infant after diazoxide.16
NEC is currently understood as a condition caused by the interaction of multiple factors, including prematurity, immune priming, and microbes (including viruses),17–20 that ultimately lead to intestinal inflammation, dysfunction, and necrosis.21–23 Although authors of recent studies have reported few cases of NEC in patients treated with diazoxide,1,10,11,16 the incidence of NEC in neonates treated with diazoxide at our center raises the possibility that, under the right combination of patient-microbiota factors, diazoxide might promote NEC in preterm neonates with HH. We hypothesize that there may be microbiota factors present in our unit, which, in combination with diazoxide, might lead to an increased risk of NEC in preterm infants. Diazoxide may inhibit acetylcholine release in the gut, consequently decreasing gastrointestinal motility24 and anti-inflammatory vagal tone,25 which have been associated with NEC. An alternative explanation is that diazoxide might reduce splanchnic perfusion as reported in infants with HH treated with octreotide who developed NEC.16,26–29
With our series, we report an increased incidence of NEC in a subset of patients with HH. All cases were infants born at or <37 weeks’ gestation, and we propose that diazoxide may need to be used cautiously in preterm infants. Ongoing multicenter data collection to study gastrointestinal effects of diazoxide in neonates with HH is warranted.
Acknowledgments
We thank our patients and their families. We thank the nurses, residents, fellows, and attending physicians involved in the care of these patients in the Massachusetts General Hospital NICU. We thank Camden P. Bay, PhD for biostatistical support through the Harvard Catalyst. We thank Brett Nelson, MD from the Department of Pediatrics at Massachusetts General Hospital for helpful discussions.
Drs Keyes, Healy, Sparger, Roumiantsev, Geha, and Matute conceptualized and designed the study, performed data collection, and drafted the manuscript; Dr Orth assisted in identifying the patients exposed to diazoxide in the NICU at Massachusetts General Hospital; and all authors reviewed and revised the manuscript and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: Supported by a grant for Quality and Safety at the MassGeneral Hospital for Children and with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541), and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Funded by the National Institutes of Health (NIH).
References
Competing Interests
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
